JPH045277A - 4,5,6,7-tetrahydrobenzimidazole derivative - Google Patents
4,5,6,7-tetrahydrobenzimidazole derivativeInfo
- Publication number
- JPH045277A JPH045277A JP10809690A JP10809690A JPH045277A JP H045277 A JPH045277 A JP H045277A JP 10809690 A JP10809690 A JP 10809690A JP 10809690 A JP10809690 A JP 10809690A JP H045277 A JPH045277 A JP H045277A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- acid
- compound
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KAWYASGZISVRAL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-benzimidazole Chemical class C1CCCC2=C1N=CN2 KAWYASGZISVRAL-UHFFFAOYSA-N 0.000 title claims 2
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 4
- 206010047700 Vomiting Diseases 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 3
- 229960004316 cisplatin Drugs 0.000 abstract description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 2
- 230000005855 radiation Effects 0.000 abstract description 2
- 230000008673 vomiting Effects 0.000 abstract description 2
- LQXRWFGXMQZLIV-UHFFFAOYSA-N 4,5,6,7-tetrahydro-3h-benzimidazol-1-ium-5-carboxylate Chemical compound C1C(C(=O)O)CCC2=C1NC=N2 LQXRWFGXMQZLIV-UHFFFAOYSA-N 0.000 abstract 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 abstract 1
- 239000002111 antiemetic agent Substances 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 230000003042 antagnostic effect Effects 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229940076279 serotonin Drugs 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- WYWNEDARFVJQSG-UHFFFAOYSA-N 2-methylserotonin Chemical compound C1=C(O)C=C2C(CCN)=C(C)NC2=C1 WYWNEDARFVJQSG-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- -1 impentyl group Chemical group 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 230000002550 fecal effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- QVVAWONRFLJUBP-UHFFFAOYSA-N 1,3-benzothiazol-3-ium;chloride Chemical compound Cl.C1=CC=C2SC=NC2=C1 QVVAWONRFLJUBP-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- XKLNOVWDVMWTOB-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1h-carbazole Chemical class N1C2=CC=CC=C2C2=C1CCCC2 XKLNOVWDVMWTOB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- 125000003858 2-ethylbutoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])O*)C([H])([H])C([H])([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- 206010002869 Anxiety symptoms Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000017228 Gastrointestinal motility disease Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical group C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- LEEYFTAQGZGGNZ-UHFFFAOYSA-N N1C(=NC=C1)C1=NC2=CC=CC=C2CN1 Chemical compound N1C(=NC=C1)C1=NC2=CC=CC=C2CN1 LEEYFTAQGZGGNZ-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000007932 benzotriazole esters Chemical class 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000000198 serotonin 5-HT3 receptor agonist Substances 0.000 description 1
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明は、医薬として有用な4.5.6.7−チトラヒ
ドロペンズイミダゾール誘導体およびその塩に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to 4.5.6.7-titrahydropenzimidazole derivatives and salts thereof useful as pharmaceuticals.
本発明の化合物は、 5−HT3拮抗作用を有する新
規化合物である。The compound of the present invention is a novel compound having 5-HT3 antagonistic activity.
(発明の背景)
従来、 5−HT3拮抗剤としては特開昭59−366
75号公報、特開昭59−67284号公報に記載のア
ザビシクロ化合物、特開昭60−214784号公報に
記載のテトラヒドロカルバゾール誘導体、特開昭61−
275276号公報に記載のアザビシクロ化合物等が知
られている。(Background of the invention) Conventionally, as a 5-HT3 antagonist, JP-A-59-366
Azabicyclo compounds described in JP-A No. 75, JP-A-59-67284, tetrahydrocarbazole derivatives described in JP-A-60-214784, JP-A-61-Sho.
Azabicyclo compounds described in Japanese Patent No. 275276 are known.
(解決手段)
本発明者らは、優れた5−HT3拮抗作用を有する化合
物の探索を目的として9種々の新規化合物を創製し、そ
のスクリーニングを進めてきたところ、下記一般式(I
)で示される4、 5.6.7テ)7ヒドロベンズイミ
ダゾ一ル誘導体が優れた5−HT3拮抗活性を有するこ
とをつきとめ。(Solution Means) The present inventors have created nine various new compounds for the purpose of searching for compounds having excellent 5-HT3 antagonistic activity, and have proceeded with their screening, and found that the following general formula (I
We have found that 4, 5.6.7) 7-hydrobenzimidazol derivatives shown in ) have excellent 5-HT3 antagonistic activity.
本発明を完成させるに至った。The present invention has now been completed.
すなわち2本発明は、一般式(I)
(式中 R1は、水素原子又は低級アルコキシ基を、A
は、 O,S、N、CH2−N ((但しR2は、水
素原子又は低級アルキル基を意味する。)又はCH=N
基を意味する。)
で示される4、5,6.7−チトラヒドロベンズイミダ
ゾール誘導体又はその塩に関する。That is, the present invention is based on the general formula (I) (wherein R1 represents a hydrogen atom or a lower alkoxy group, A
is O, S, N, CH2-N ((However, R2 means a hydrogen atom or a lower alkyl group) or CH=N
means base. ) The present invention relates to a 4,5,6,7-titrahydrobenzimidazole derivative or a salt thereof.
本明細書の一般式の基の定義において「低級」とは、特
に断らない限り炭素数1乃至6個を有する直鎖又は分岐
状の炭素鎖を意味する。In the definition of the group in the general formula herein, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.
従って、「低級アルキル基」としてはメチル基、エチル
基、プロピル基、ブチル基、ペンチル基、ヘキシル基、
インプロピル基、イソブチル基、 tert−ブチル
基、インペンチル基、 tert −ペンチル基、イン
ヘキシル基等が挙げられる。Therefore, "lower alkyl groups" include methyl, ethyl, propyl, butyl, pentyl, hexyl,
Examples include inpropyl group, isobutyl group, tert-butyl group, impentyl group, tert-pentyl group, inhexyl group, and the like.
「低級アルコキシ基」としてメトキシ基ツ エトキシ基
、プロポキシ基、ブトキシ基、ペンチルオキシ基、ヘキ
シルオキシ基、インフロポキシ基、インブトキシ基、
tert−ブトキシ基、 イソペンチルオキシ基、
tert−ペンチルオキシ基。"Lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, infropoxy group, imbutoxy group,
tert-butoxy group, isopentyloxy group,
tert-pentyloxy group.
イソヘキシルオキン基、2−エチルブトキシ基等が挙げ
られる。Examples include isohexyl oxyne group and 2-ethylbutoxy group.
また9本発明化合物は塩を形成することもできる。かか
る塩としては2例えば塩酸、臭化水素酸、ホウ酸、リン
酸、硫酸等の無機酸との塩並びに酢酸、酒石酸、マレイ
ン酸、フマル酸。The compounds of the present invention can also form salts. Such salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid, sulfuric acid, as well as acetic acid, tartaric acid, maleic acid, fumaric acid.
クエン酸、コハク酸、安息香酸、p−トルエンスルホン
酸等の有機酸との塩が挙げられる。Examples include salts with organic acids such as citric acid, succinic acid, benzoic acid, and p-toluenesulfonic acid.
更に2本発明化合物はテトラヒドロイミダゾール骨格を
有しており、また分子中に不整炭素原子を有しており、
一般式(I)に含まれる化合物には互変異性体や不整炭
素原子に基づく光学異性体などの異性体が存在する。Furthermore, two of the compounds of the present invention have a tetrahydroimidazole skeleton and an asymmetric carbon atom in the molecule,
The compound included in the general formula (I) has isomers such as tautomers and optical isomers based on asymmetric carbon atoms.
本発明にはこれら異性体の単離されたものあるいは混合
物が含まれる。The present invention includes isolated or mixtures of these isomers.
以下に本発明化合物の製造法について具体的に説明する
。The method for producing the compound of the present invention will be specifically explained below.
製法1゜
(式中AおよびR1は前記と同じ意味を表わす。)本発
明化合物(I)は、一般式(I[)で示されるアニリン
誘導体に式(III)で示される4、5.6.7−テト
ラヒドロベンズイミダゾール−5−カルボン酸又はその
反応性誘導体を反応させることにより得ることができる
。Production method 1゜ (In the formula, A and R1 represent the same meanings as above.) The compound (I) of the present invention is an aniline derivative represented by the general formula (I[), and 4,5.6 represented by the formula (III). It can be obtained by reacting 7-tetrahydrobenzimidazole-5-carboxylic acid or a reactive derivative thereof.
化合物(n)と化合物(III)またはその反応性誘導
体との反応は2通常溶媒中室温乃至加温下で行われる。The reaction between compound (n) and compound (III) or its reactive derivative is usually carried out in a solvent at room temperature to elevated temperature.
溶媒は反応に関与しない溶媒であれば特に制限はない。The solvent is not particularly limited as long as it does not participate in the reaction.
通常使用されるものとしては、アセトン、ジオキサン、
エーテル、テトラヒドロフラン、メチルエチルケトン、
クロロホルム、ジクロロエタン、ジクロロメタン、酢酸
エチル、ギ酸エチル、ジメチルホルムアミド。Commonly used ones include acetone, dioxane,
ether, tetrahydrofuran, methyl ethyl ketone,
Chloroform, dichloroethane, dichloromethane, ethyl acetate, ethyl formate, dimethylformamide.
ジメチルスルホキシド等が挙げられる。これらの溶媒は
適宜混合して使用してもよい。Examples include dimethyl sulfoxide. These solvents may be mixed and used as appropriate.
化合物(m)は遊離カルボン酸の状態で使用されるほか
、カルボン酸の反応性誘導体として反応に供される。カ
ルボン酸の反応性誘導体としては活性エステル(たとえ
ばベンゾトリアゾールエステルなど)、混合酸無水物、
酸ハロゲン化物、活性アミド、酸無水物、酸アジド等が
用いられる。Compound (m) is used in the form of a free carboxylic acid or is subjected to a reaction as a reactive derivative of a carboxylic acid. Reactive derivatives of carboxylic acids include active esters (such as benzotriazole esters), mixed acid anhydrides,
Acid halides, activated amides, acid anhydrides, acid azides, etc. are used.
化合物(III)を遊離のカルボン酸の状態で使用する
ときは、N、N’−ジシクロへキシルカルボジイミド、
N、N’−ジエチルカルボジイミド等の縮合剤で縮
合後、必要があれば、硫酸、ポIJ リン酸等の脱水剤
を使用するか、直接、硫酸、ポリリン酸等の脱水剤を使
用するのが好ましい。When compound (III) is used in the form of free carboxylic acid, N,N'-dicyclohexylcarbodiimide,
After condensation with a condensing agent such as N,N'-diethylcarbodiimide, if necessary, use a dehydrating agent such as sulfuric acid or polyphosphoric acid, or directly use a dehydrating agent such as sulfuric acid or polyphosphoric acid. preferable.
また用いられるカルボン酸の反応性誘導体の種類によっ
ては、塩基の存在下に反応させるのが2反応を円滑に進
行させる上で好ましい場合もある。かかる塩基としては
炭酸水素ナト+7ウム、炭酸水素カルラム、炭酸ナトリ
ウム、炭酸カリウム等の無機塩基、トリメチルアミン、
トリエチルアミン、ジメチルアニリン、ピリジン等の有
機塩基が挙げられる。Depending on the type of reactive derivative of carboxylic acid used, it may be preferable to carry out the reaction in the presence of a base in order to allow the two reactions to proceed smoothly. Such bases include inorganic bases such as sodium hydrogen carbonate+7um, carrum hydrogen carbonate, sodium carbonate, potassium carbonate, trimethylamine,
Examples include organic bases such as triethylamine, dimethylaniline, and pyridine.
製法(n)
本製造法は、一般式(Ib)で示される化合物(一般式
(I)の化合物においてAがCH=N基を意味する化合
物)を製造する方法である。化合物(Ib)は化合物(
JV)を酸化して製造することができる。Production method (n) This production method is a method for producing a compound represented by general formula (Ib) (a compound in which A means a CH═N group in the compound of general formula (I)). Compound (Ib) is a compound (
JV) can be produced by oxidizing it.
化合物(IV)の酸化は2通常の方法により行うことが
できる。たとえば四酢酸鉛、二酸化マンガン等の酸化剤
により;イオウ、セレン等の金属により;又は触媒的酸
化による。触媒的酸化(脱水素化)剤としては、ふつう
パラジウム。Oxidation of compound (IV) can be carried out by two conventional methods. For example by oxidizing agents such as lead tetraacetate, manganese dioxide; by metals such as sulfur, selenium; or by catalytic oxidation. The catalytic oxidation (dehydrogenation) agent is usually palladium.
白金、ロジウムのような触媒が利用できる。Catalysts such as platinum and rhodium can be used.
この反応は通常、たとえば水、アルコール(たとえばメ
タノール、エタノール等)、デカリン、ベンゼン等又は
その混合物のような。This reaction typically involves, for example, water, alcohols (eg methanol, ethanol, etc.), decalin, benzene, etc. or mixtures thereof.
反応に悪影響を及ぼさな(・ような溶媒中で行なうか、
あるいは無溶媒でも行うことができる。It should be carried out in a solvent that does not adversely affect the reaction.
Alternatively, it can be carried out without a solvent.
反応温度は臨界的なものではなく、この反応は通常は加
熱下で行われる。The reaction temperature is not critical, and the reaction is usually carried out under heat.
このようにして製造された本発明化合物は遊離のままあ
るいはその塩として単離され精製される。単離、精製は
、抽出、結晶化、再結晶。The compound of the present invention thus produced is isolated and purified in its free form or as a salt thereof. Isolation and purification include extraction, crystallization, and recrystallization.
各種クロマトグラフィー等の通常の化学操作を適用して
行われる。This is carried out by applying ordinary chemical operations such as various chromatography.
また、ラセミ化合物は適当な原料化合物を用いることに
より、あるいは一般的なラセミ分割法により[たとえば
、一般的な光学活性酸(酒石酸等)とのジアステレオマ
ー塩に導き、光学分割する方法等]立体化学的に純粋な
異性体に導くことができる。Racemic compounds can also be obtained by using appropriate raw materials or by general racemic resolution methods [for example, a method of optically resolving a diastereomer salt with a general optically active acid (tartaric acid, etc.)] can lead to stereochemically pure isomers.
(発明の効果)
本発明化合物又はその塩は麻酔ラットにおいてセロトニ
ンによる一過性の徐脈を特異的に抑制したことから5−
HT3拮抗作用を有することが確認された。従って2本
発明化合物はシスプラチンなどの制癌剤および放射線に
よる嘔吐を抑制し、扁頭痛、複合頭痛、三叉神経痛、不
安症状、胃腸運動障害、消化性潰瘍、過敏性腸症候群等
の予防・治療に有用であると考えられる。(Effect of the invention) The compound of the present invention or a salt thereof specifically inhibited serotonin-induced transient bradycardia in anesthetized rats.
It was confirmed that it has HT3 antagonistic effect. Therefore, the compounds of the present invention suppress vomiting caused by anticancer drugs such as cisplatin and radiation, and are useful for the prevention and treatment of migraines, compound headaches, trigeminal neuralgia, anxiety symptoms, gastrointestinal motility disorders, peptic ulcers, irritable bowel syndrome, etc. It is believed that there is.
本発明化合物の薬理効果は9次の様にして確認されたも
のである。The pharmacological effects of the compounds of the present invention were confirmed in the following manner.
1) 5−)IT3受容体拮抗作用
生後9週令のウィスター(Wister )系雄性ラッ
トをウレタン1g/kgの腹腔内投与により麻酔し9人
工呼吸上血圧および心拍数を測定した。セロトニンある
いは5− HT3の選択的作動薬である2−メチルセロ
トニンを静脈内投与することにより起こる一過性の心拍
数の減少および血圧の下降を5− HT3受容体を介し
た反応の指標とした( Bezold−Jarish反
射;Pa1ntal A、 S、、 Physiol、
Rev、+ 53+ 159+ 1973 )。1) 5-) IT3 receptor antagonism Nine-week-old male Wistar rats were anesthetized by intraperitoneal administration of urethane at 1 g/kg, and blood pressure and heart rate during 9 artificial breaths were measured. The transient decrease in heart rate and blood pressure caused by intravenous administration of serotonin or 2-methylserotonin, a selective 5-HT3 agonist, was used as an indicator of a response mediated by 5-HT3 receptors. (Bezold-Jarish reflex; Palintal A, S, Physiol,
Rev. +53+159+1973).
本発明化合物又はその塩は、セロトニンおよび2−メチ
ルセロトニン投与の10分前に静脈内投与(0,03〜
3μg/ kg )あるいは60分前に経口投与(1〜
30μg/kg)することにより。The compound of the present invention or a salt thereof is administered intravenously 10 minutes before administration of serotonin and 2-methylserotonin (0.03-
3μg/kg) or oral administration 60 minutes before
30 μg/kg).
セロトニンおよび2−メチルセロトニン投与る心拍数の
減少および血圧の下降を用量依存的に抑制した。Administration of serotonin and 2-methylserotonin inhibited the decrease in heart rate and blood pressure in a dose-dependent manner.
2)制癌剤誘発嘔吐抑制作用
体重1〜1.5 kgの雄性フエレノトに9本発明化合
物001〜0.3111g/kgを皮下あるいは経口投
与することにより、シスプラチン10■/kg腹腔内投
与により発現する嘔吐は抑制された。2) Anticancer drug-induced emesis suppressive effect Subcutaneous or oral administration of 001 to 0.3111 g/kg of the 9 compounds of the present invention to male phelenots weighing 1 to 1.5 kg suppresses the emesis induced by intraperitoneal administration of cisplatin 10 μ/kg. was suppressed.
3)ストレス便排出抑制作用
生後9週令のウィスター(Wister )系雄性ラッ
ト抱束ストレス用ケージに収容し、排出される便の数を
測定した。3) Effect on suppressing stressed fecal excretion Nine-week-old male Wistar rats were housed in cages for stress stress, and the number of feces excreted was measured.
本発明化合物又はその塩は、静脈内投与(1〜100μ
g/kg)することにより、抱束ストレスによる便排出
の光通を用量依存的に抑制した。The compound of the present invention or a salt thereof can be administered intravenously (1 to 100μ
g/kg) inhibited the phototransmission of fecal excretion caused by hugging stress in a dose-dependent manner.
(実施例) 以下に実施例を掲記し9本発明を更に詳細に説明する。(Example) EXAMPLES The present invention will be described in further detail with reference to Examples below.
実施例 1 ・H2SO。Example 1 ・H2SO.
0−アミノベンジルアミン(o2sg)を、あらかじめ
4,5,6.7−チトラヒドロペンズイミダゾールー5
−カルボン酸・硫酸塩(o、s3g)と塩化チオニル(
2mZ)より調製した酸クロリドのジメチルホルムアミ
ド(5mt)溶液に、室温上少量ずつ加え。0-Aminobenzylamine (o2sg) was pretreated with 4,5,6.7-titrahydropenzimidazole-5.
- Carboxylic acid/sulfate (o, s3g) and thionyl chloride (
Add it little by little at room temperature to a dimethylformamide (5mt) solution of acid chloride prepared from 2mZ).
終夜撹拌した。反応液に水を加え、IN水酸化ナトリウ
ムでpH8とし、溶媒を減圧下濃縮した。Stir overnight. Water was added to the reaction solution, the pH was adjusted to 8 with IN sodium hydroxide, and the solvent was concentrated under reduced pressure.
残渣のエタノール可溶分をr過し溶媒を濃縮する操作を
2回繰り返し、得られた結晶をメタノール−ジクロロメ
タンより再結晶して、 2− (4,5,6゜7−テ
トラヒドロ−5−ベンズイミダゾリル)−3,4−ジヒ
ドロキナゾリンを0.41g(81%)得た。The operation of filtering the ethanol-soluble portion of the residue and concentrating the solvent was repeated twice, and the obtained crystals were recrystallized from methanol-dichloromethane to form 2-(4,5,6°7-tetrahydro-5-benz). 0.41 g (81%) of imidazolyl-3,4-dihydroquinazoline was obtained.
・融点 210−214℃(dec、)・NMR(DM
SO−a6)
δ: 1.57−2.23(2H,m)、 2.23−
2.85(5H,m)。・Melting point 210-214℃ (dec,) ・NMR (DM
SO-a6) δ: 1.57-2.23 (2H, m), 2.23-
2.85 (5H, m).
3.38(LH,br)、 4.47(2H,s)、
6.65−7.24(5H,m)、 7.39(IH,
s)#MS : rn/z 252 (M+)実施例
2
実施例1と同様にして次の化合物を得た。3.38 (LH, br), 4.47 (2H, s),
6.65-7.24 (5H, m), 7.39 (IH,
s) #MS: rn/z 252 (M+) Example
2 The following compound was obtained in the same manner as in Example 1.
1−メチル−2−(4,5,6,7−チトラヒドロペン
ズイミダゾールー5−イル)ベンズイミダゾール骨1,
57マル酸塩
拳融点 209−211℃(MeOH−CH3CN )
・元素分析値(Cl5H16N4・1.5 C4H40
4・0.lH2Oとして)C(%) H(%)
N(%)計算値 58.90 5.23 13.
08実験値 58.68 5.30 13.38
4 MS : m/z 252 (M+、フリ一体とし
て)実施例 3
5−(4−メトキシ−2−ペンズイミタ“ゾリル)−4
,5,6,7−チトラヒドロベンズイミダゾール・05
フマル酸塩
・融点 193−195°C(MeOHCH3CN )
・元素分析値(Cl5H111N40・0.5c4H4
o4・1.5rH20として)C(%) H(%)
N(%)計算値 57.78 5.99
15.85実験値 57,87 5.69 15
.69・MS : m/s 268 (M”、フリ一
体として)実施例 4
ンクロリドーメタノール混合溶媒を用いてシリカゲルカ
ラムクロマトグラフィーで精製し、酢酸エチル中の塩酸
で処理すると融点277−280℃を示す、 2−
(4,5,6,7−チトラヒドロペンズイミダゾールー
5−イル)ベンズオキサゾール塩酸塩0.6gを得た。1-Methyl-2-(4,5,6,7-titrahydropenzimidazol-5-yl)benzimidazole bone 1,
57 malate salt melting point 209-211℃ (MeOH-CH3CN)
・Elemental analysis value (Cl5H16N4・1.5 C4H40
4.0. (as lH2O) C (%) H (%)
N (%) Calculated value 58.90 5.23 13.
08 experimental value 58.68 5.30 13.38
4 MS: m/z 252 (M+, as a free unit) Example 3 5-(4-methoxy-2-penzimita "zolyl)-4"
,5,6,7-titrahydrobenzimidazole 05
Fumarate, melting point 193-195°C (MeOHCH3CN)
・Elemental analysis value (Cl5H111N40・0.5c4H4
o4・1.5rH20) C (%) H (%)
N (%) Calculated value 57.78 5.99
15.85 Experimental value 57,87 5.69 15
.. 69・MS: m/s 268 (M", as a free unit) Example 4 Purified by silica gel column chromatography using a chloride-methanol mixed solvent and treated with hydrochloric acid in ethyl acetate, showing a melting point of 277-280°C , 2-
0.6 g of (4,5,6,7-titrahydropenzimidazol-5-yl)benzoxazole hydrochloride was obtained.
・元素分析値(cl4 H14N30CIとして)C(
%)H(%) N(%)cl(%)計算値 60,9
8 5.12 15.24 12.86実験値 60.
74 5.03 15.16 12.97・マススペク
トル(El): m/z 239(M+、7リーベー
スとして)4.5,6.7−チトラヒドロベンズイミダ
ンールー5−カルボン酸1.32gおよびオルトアミノ
フェノール0.6gをポリリン酸SmZ中、 170−
180℃で1時間処理した。反応液に氷水100m1を
加え、炭酸カリウムでアルカリ性とした後、メチレンク
ロリドで抽出した。メチレンクロリド層を無水硫酸マグ
ネシウムで乾燥後、減圧濃縮し、残渣をメチレ実施例
5
実施例4と同様にして次の化合物を得た。・Elemental analysis value (as cl4 H14N30CI) C(
%) H (%) N (%) cl (%) Calculated value 60.9
8 5.12 15.24 12.86 Experimental value 60.
74 5.03 15.16 12.97 Mass spectrum (El): m/z 239 (M+, as 7-li base) 4.5,6.7-titrahydrobenzimidan-5-carboxylic acid 1. 32 g and 0.6 g of orthoaminophenol in polyphosphoric acid SmZ, 170-
It was treated at 180°C for 1 hour. 100 ml of ice water was added to the reaction solution, the mixture was made alkaline with potassium carbonate, and then extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was converted into methylene chloride Example.
5 The following compound was obtained in the same manner as in Example 4.
2− (4,5,6,7−チトラヒドロペンズイミタゾ
ールー5−イル)ベンゾチアゾール塩酸塩・融点 26
5−268℃(分解)
核磁気共鳴スペクトル(DMSO−d6) ’δ: 2
.00−3.80(7H,m)、 7.30−8.20
(4H,m)。2-(4,5,6,7-titrahydropenzimitazol-5-yl)benzothiazole hydrochloride, melting point 26
5-268℃ (decomposition) Nuclear magnetic resonance spectrum (DMSO-d6) 'δ: 2
.. 00-3.80 (7H, m), 7.30-8.20
(4H, m).
8.97 (I H,s )
マススペクトル(EI) : m/s 255 (M
+、フリーペースとして)元素分析値(Cl5H14N
4・C,1(40,として)C(%) H(%)
N(%)計算値 62,29 4.95 1
5.29実験値 62,02 4.88 15.2
5M5 : m/z 250 (M+、フリ一体とし
て)実施例 6
2− (4,5,6,7−テトラヒドロ−5−ペンズイ
ミタ゛ゾリル) −3,4−ジヒドロキナゾリン(0,
45g)と5%パラジウム−炭素(0,45g)のメタ
ノール(15+nl)混合液を終夜加熱還流した。反応
液をf通抜、減圧下濃縮し、残渣をシリカゲルカラムク
ロマトグラフィー(1sg)に付した。10%メタノー
ル−クロロホルムで溶出し、 2− (4,5,6,
7−テトラヒドロ−5−ベンズイミダゾリル)キナゾリ
ンをo、osg(18%)得、これをフマル酸塩とした
。8.97 (I H,s) Mass spectrum (EI): m/s 255 (M
+, as free pace) elemental analysis value (Cl5H14N
4・C,1 (as 40) C (%) H (%)
N (%) Calculated value 62,29 4.95 1
5.29 Experimental value 62.02 4.88 15.2
5M5: m/z 250 (M+, as a free integral) Example 6 2- (4,5,6,7-tetrahydro-5-penzimitazolyl) -3,4-dihydroquinazoline (0,
A mixture of 5% palladium-carbon (0.45 g) and 5% palladium-carbon (0.45 g) in methanol (15+nl) was heated under reflux overnight. The reaction solution was passed through f and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (1 sg). Elute with 10% methanol-chloroform, 2-(4,5,6,
7-tetrahydro-5-benzimidazolyl) quinazoline was obtained in an amount of 18%, which was used as the fumarate salt.
・融点 188−189℃(Me OH−CH3CN
)特許出願人 山之内製薬株式会社
代理人 弁理士 長 井 省 三・Melting point 188-189℃ (Me OH-CH3CN
) Patent applicant Yamanouchi Pharmaceutical Co., Ltd. Agent Patent attorney Shozo Nagai
Claims (1)
は、O、S、N、▲数式、化学式、表等があります▼(
(但しR^2は水素原子又は低級アルキル基を意味する
))又はCH=N基を意味する。) で示される4,5,6,7−テトラヒドロベンズイミダ
ゾール誘導体又はその塩。[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a lower alkoxy group,
There are O, S, N, ▲mathematical formulas, chemical formulas, tables, etc.▼(
(However, R^2 means a hydrogen atom or a lower alkyl group)) or means a CH=N group. ) A 4,5,6,7-tetrahydrobenzimidazole derivative or a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10809690A JPH045277A (en) | 1990-04-24 | 1990-04-24 | 4,5,6,7-tetrahydrobenzimidazole derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10809690A JPH045277A (en) | 1990-04-24 | 1990-04-24 | 4,5,6,7-tetrahydrobenzimidazole derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH045277A true JPH045277A (en) | 1992-01-09 |
Family
ID=14475774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10809690A Pending JPH045277A (en) | 1990-04-24 | 1990-04-24 | 4,5,6,7-tetrahydrobenzimidazole derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH045277A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6271589B1 (en) | 1996-06-27 | 2001-08-07 | Asahi Kasei Kabushiki Kaisha | Thick-film conductor circuit and production method therefor |
-
1990
- 1990-04-24 JP JP10809690A patent/JPH045277A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6271589B1 (en) | 1996-06-27 | 2001-08-07 | Asahi Kasei Kabushiki Kaisha | Thick-film conductor circuit and production method therefor |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4964380B2 (en) | Tricyclic derivative of pyrazole carboxylic acid, process for producing the same and pharmaceutical composition containing the same | |
US5929089A (en) | 5-phenyl-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one derivatives for use as 5-Ht4 or H3 receptor ligands | |
AU671836B2 (en) | Fused imidazole and triazole derivatives as 5-HT1 receptor agonists | |
JP2898139B2 (en) | Cyclic diamine compound and its intermediate | |
PT862567E (en) | 5-AZABICYCLO (3.1.0) HEXILALQUIL-2-PIPERIDONES AND -GLUTARIMIDES AS ANTAGONISTS OF THE NEUROCININE RECEPTOR | |
JP4982886B2 (en) | New azetidine compounds | |
KR100340145B1 (en) | Benzezepine derivatives and intermediates thereof | |
PL198857B1 (en) | Piperazine and piperidine compounds | |
JPH02138266A (en) | 6-phenyl-3-(piperazinylalkyl)-2,4(1h,3h)-pyrimidine dione derivative | |
US4977175A (en) | 4,5,6,7-tetrahydrobenzimidazole derivatives as 5HT3 -antagonists | |
JP3775823B2 (en) | Novel imide derivatives | |
AU702285B2 (en) | New indole, indazole benzisoxazole compounds, their process of preparation and the pharmaceutical compositions which contain them | |
EP0636131A1 (en) | Heteroaromatic 5-hydroxytryptamine receptor agonists | |
WO1993020066A1 (en) | Imidazole, triazole and tetrazole derivatives | |
JPH045277A (en) | 4,5,6,7-tetrahydrobenzimidazole derivative | |
US5449787A (en) | N,N'-disubstituted amide derivatives | |
JPH06157518A (en) | New oxadiazole derivative or its salt | |
US5736558A (en) | 4-(6-fluoro-1,2-benzisoxazolyl)-1 piperidinyl-propoxy-chromen-4-one-one-derivatives, their preparation and their use in the treatment of psychosis, schizophrenia and anxiety | |
US5166341A (en) | 6-amino-1,4-hexahydro-1H-diazepine derivatives | |
JPH0413666A (en) | 1-(alkoxyphenyl)-3-(4,5,6,7-tetrahydrobenzimidazolyl)urea | |
EP1222185A1 (en) | Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists | |
HU198023B (en) | Process for production of new derivatives of benzamid and medical preparatives containing these compounds as active substance | |
JPH04352770A (en) | Aminoalkylthiazole derivative | |
JPH03218362A (en) | 4,5,6,7-tetrahydrobenzimidazole derivative and medicine containing the same | |
Leeson et al. | Transannular reactions of 5-azido-and 5-nitronodibenzo [a, e] cyclooctatrienes and-dibenzo [a, d] cycloheptatrienes. Syntheses of pavine and homoisopavine analogs |